Regenerative therapies may be used in the replenishment of damaged tissues/organs caused by chemotherapy or radiotherapy, associated with degenerative diseases or aging.
Conventional regenerative therapies commonly rely on the introduction of donor-derived regenerative cells and/or the administration of biologically active molecules that stimulate regeneration. Besides ethical issues, technical and safety challenges in stem cell isolation, maintenance, expansion, donor-recipient matching and transplantation persist and limit the usefulness and practicability of existing conventional regenerative therapies. Conventional therapies typically have not utilized dietary protocol has effective treatments for patients in need of tissue regeneration. Although diet has been known to provide tissue protection in various circumstances. The major limitation of conventional therapies is the lack of a coordinated regenerative process that is reminiscent of the developmental process leading to tissue generation in the embryo. The formulations and methods described in this application can overcome these limitations.
Caloric Restriction (CR) without malnutrition is effective in protecting the brain against aging and oxidative stress (Martin et al. 2006). Several studies support a beneficial role for this dietary intervention in protecting against age dependent decay in cognitive performance in rodents (Fontan-Lozano et al. 2008). In addition CR shows remarkable neuroprotective properties against neurodegenerative diseases including stroke, Parkinson's disease (PD), Huntington's disease (HD) and Alzheimer's Disease (AD) in several animal models (Mattson 2005; Patel et al. 2005).
Recent studies in different AD mouse models reported that reducing food intake can diminish AD-related neuropathologies and cognitive dysfunction. For example, CR reduces the progression of β amyloid (Aβ) deposition in the hippocampus and cerebral cortex of AD mice carrying mutations for FAD (Wang et al. 2005), APP (amyloid precursor protein) and APP+PS-1 (presenilin 1) (Patel et al. 2005; Mouton et al. 2009). CR ameliorates neurodegenerative phenotypes assessed by object recognition and contextual fear conditioning tests in cDKO (conditional double knockout) AD mice (Wu et al. 2008). Mattson and coworkers have shown that CR can also ameliorate age-related memory impairment and decrease Aβ and phosphorylated tau accumulation in a triple transgenic mouse (3×Tg-AD) that overexpress mutations linked to AD (PS-1, APP) and frontotemporal dementia (tau) (Halagappa et al. 2007). Also studies in human populations suggest that diet plays an important role in AD and reduced food intake may protect against this pathology. For example, an epidemiological study by Luchsinger and colleagues provided evidence that individuals with a low calorie intake have a reduced risk of developing AD (Luchsinger et al. 2002).
Among the large number of metabolic and physiological changes caused by CR, reduction of growth hormone (GH)/insulin-like factor (IGF-1) signaling axis may be important for its protective effects (Fontana et al. 2010). Circulating IGF-1 is a hormone produced primarily by the liver that regulates energy metabolism, cell proliferation, cell differentiation, body size and longevity. IGF-1 levels are regulated by calorie and/or protein availability and long-term CR decreases serum IGF-1 concentration by approximately 30-40% in rodents (Thissen et al. 1994) but not in humans unless protein intake is also reduced (Fontana et al. 2008). Mutations that decrease the activity of the growth hormone receptor (GHR)/IGF-1 signaling pathways, similarly to CR, can extend longevity and enhance stress resistance in a wide range of organisms and tissues (Kenyon 2005) including mammalian central nervous system (CNS) (Parrella & Longo 2010). Although the overlap between the pathways altered by these nutritional and genetic interventions seems to be only partial, it has been proposed that the decline in IGF-1 levels can mediate part of the beneficial effects produced by CR (Sonntag et al. 1999). In support of this theory, recently it has been shown that reducing IGF-1 signaling in an AD mouse carrying APP and PS-1 mutations protects against Alzheimer's-like disease symptoms including cognitive deficits and neuroinflammation (Cohen et al. 2009). Notably, GH receptor-deficient (GHRD) mice and humans are protected from major diseases (Guevara-Aguirre et al. 2011; Ikeno et al. 2009; Masternak et al. 2009) and GHRD mice consistently live 40% longer (Coschigano et al. 2000). Moreover, a study carried out on a cohort of Ashkenazi Jewish centenarians identified genetic alterations on human IGF-1 receptor (IGF-1R) that result in reduced IGF-1 signaling among the centenarians compared to controls (Suh et al. 2008). On the other hand the effect of IGF-1 or IGF-1R deficiency on lifespan is inconsistent (Bokov et al. 2011), suggesting that reduced IGF-1 may be only one of the mediators of the anti-aging effects of GHR deficiency.
Protein and amino acid (AA) availability is fundamental in regulating IGF-1 gene expression. Moreover, protein restriction not only decreases IGF-1 production rate, but also accelerates its clearance, regulates IGF-1 interaction with IGF binding proteins (IGFBPs) and attenuates IGF-1 biological actions (Ketelslegers et al. 1995). Because CR is very difficult to maintain, and is unavoidably associated with weight loss, loss of sex drive, hunger, feeling cold at normal room temperature and possible immune system side effects.
Accordingly, there is a need for dietary protocols to alleviate symptoms of Alzheimer's disease and/or other degenerative diseases and to promote tissue regeneration.